Abstract

Parkinson's disease (PD) represents one of the most prevalent age‑related neurodegenerative movement disorders worldwide, characterised by progressive loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Clinical manifestations include classic motor symptoms such as resting tremor, muscular rigidity, bradykinesia, postural instability, alongside diverse non‑motor complications including gastrointestinal dysfunction, sleep disturbance, cognitive impairment and mental disorder. Current clinical therapeutic strategies predominantly rely on symptomatic agents such as levodopa, dopamine receptor agonists, MAO‑B inhibitors and COMT inhibitors. Nevertheless, long‑term medication frequently triggers adverse reactions including on‑off phenomenon, dyskinesia and psychiatric disturbances. There remains an unmet clinical demand for disease‑modifying therapeutic candidates with improved safety profiles.

Cistanche deserticola, commonly nicknamed "desert ginseng", is a well‑documented food‑medicine homologous parasitic herb originating from desert ecosystems of Northwest China. In traditional herbal systems, it is applied for tonifying kidney‑yang, replenishing essence‑blood and relieving constipation. Modern pharmacological investigations have verified that its principal bio‑active fractions, primarily phenylethanol glycosides (PhGs) represented by echinacoside and verbascoside, together with polysaccharides and galactitol, exert multi‑target neuroprotective effects for PD pathology. These bio‑constituents safeguard dopaminergic neurons by ameliorating mitochondrial dysfunction, suppressing neuroinflammatory cascades, mitigating endoplasmic reticulum stress, restraining oxidative injury, remodelling gut microbial composition and inhibiting pathological neuronal apoptosis.

This systematic review synthesises recent pre‑clinical in‑vitro cellular and in‑vivo animal studies concerning PD‑relevant neuroprotective activities of Cistanche deserticola derived compounds. It elaborates corresponding molecular signalling pathways, interprets existing research limitations and highlights prospective research directions. This work aims to provide consolidated theoretical references for further basic exploration and translational development of natural neuroprotective botanical agents for Parkinson's disease intervention.

Keywords: Cistanche deserticola; Parkinson's disease; echinacoside; verbascoside; phenylethanol glycosides; neuroprotection; mitochondrial dysfunction; neuroinflammation; endoplasmic reticulum stress; gut‑brain axis; neuronal apoptosis

1. Introduction

Parkinson's disease is a chronic, progressive neurodegenerative illness imposing heavy socioeconomic burdens across global ageing populations. Epidemiological data indicate that worldwide PD patients have exceeded six million individuals, predominantly middle‑aged and elderly demographics. The disease incidence reaches 0.7 ‰ among people older than 50 years, rising to 3 %‑5 % within populations aged over 60 years. To date, the complete aetiology of PD has not been fully clarified. The prevailing pathological viewpoints attribute dopaminergic neuronal degeneration and death to multiple interconnected pathogenic drivers, encompassing neuroinflammatory responses, mitochondrial functional defects, endoplasmic reticulum stress, excessive oxidative stress, programmed cell apoptosis and gut microbiota dysbiosis.

Available clinical pharmaceuticals can only alleviate symptomatic manifestations rather than halt or reverse disease progression. Chronic administration brings notable side‑effect risks, which motivates extensive research interest in natural plant‑derived neuroprotective substances from traditional herbal medicine resources.

Cistanche deserticola Y. C. Ma belongs to Orobanchaceae family, an obligate holoparasitic herb without chlorophyll, parasitising the root system of desert shrub Haloxylon ammodendron. Its fleshy scaly stem has been recorded in classical Chinese herbal monographs including Shen‑Nong‑Ben‑Cao‑Jing, classified as high‑grade tonic botanical material. It carries multiple aliases such as great‑yun, golden bamboo and earth spirit. According to ancient herbal theories, this herb is warm‑natured, with sweet‑salty flavour, acting upon kidney and large‑intestine meridians, exhibiting tonifying kidney‑yang, benefiting essence‑blood, moistening intestines to treat constipation pharmacological attributes. In recent decades, growing pre‑clinical evidence demonstrates that extracts and purified monomer compounds isolated from Cistanche deserticola deliver promising neuroprotective potency against PD‑related pathological damage.

Major bio‑active chemical constituents isolated from Cistanche deserticola comprise phenylethanol glycosides, polysaccharides, galactitol and flavonoid derivatives. Among these substances, echinacoside and verbascoside are the most intensively investigated markers within PD‑oriented pharmacological research. Accumulated cellular and animal experimental outputs reveal that these ingredients intervene in PD pathological progress through multi‑pathway synergistic regulation: restoring impaired mitochondrial function, repressing microglia‑mediated neuroinflammation, relieving endoplasmic reticulum stress, counteracting oxidative stress injury, modulating gut microbial communities and suppressing dopaminergic neuron apoptosis.

This review systematically organises contemporary pre‑clinical research literature regarding neuroprotective mechanisms of Cistanche deserticola bio‑components against Parkinson's disease. It summarises respective molecular signalling pathways, analyses current experimental bottlenecks and points out gaps for follow‑up translational research. It is expected to offer theoretical foundations for future mechanism exploration and new drug development of botanical neuroprotective agents targeting Parkinson's disease.

2. Core Pathogenic Mechanisms of Parkinson's Disease

2.1 Mitochondrial dysfunction

Mitochondrial dysfunction is widely regarded as one of the key initiating factors triggering the loss of substantia nigra dopaminergic neurons. Familial PD‑associated PARK gene mutations frequently induce defects in mitochondrial quality‑control systems, especially mitophagy pathways. Genetically modified animal models exhibiting impaired mitophagy manifest multiple pathological phenotypes highly similar to Parkinson's disease. Mitochondrial complex‑I activity reduction, disrupted mitochondrial membrane potential and excessive reactive oxygen species (ROS) overproduction jointly aggravate neuronal oxidative damage, forming a vicious cycle that accelerates dopaminergic neuron degeneration.

2.2 Neuroinflammatory activation

Persistent neuroinflammatory response occupies a central position in PD pathological evolution. Over‑activated microglia and astrocytes release abundant pro‑inflammatory mediators including TNF‑α, IL‑1β, IL‑6 upon pathological stimulation. These inflammatory cytokines generate toxic insults towards surrounding dopaminergic neurons. Multiple signalling cascades participate in this inflammatory process, covering p38 MAPK, NF‑κB and NLRP3‑inflammasome signalling axes. Sustained glial over‑activation further amplifies neurotoxic micro‑environment and exacerbates neurodegenerative progression.

2.3 Endoplasmic reticulum stress

Endoplasmic reticulum (ER) undertakes protein folding and processing tasks within neurons. Pathological stimuli induce accumulation of misfolded proteins inside ER lumen, triggering endoplasmic reticulum stress (ERS). If stress cannot be alleviated, ERS will initiate downstream pro‑apoptotic signal transduction and ultimately provoke neuronal death. Mutations of seipin ER‑membrane protein can induce misfolded‑protein aggregation and aggravate ER stress injury, which is closely correlated with dopaminergic neuron loss in PD pathology. Biomarkers such as GRP78 and MANF serve as important molecular indicators to evaluate ER‑stress severity in neuronal injury models.

2.4 Oxidative‑stress injury

Oxidative stress emerges at the early phase of PD pathological progression. Excess ROS attack lipid, protein and nucleic acid molecules inside nerve cells, causing biomacromolecule damage. Mutations of DJ‑1 gene linked with familial Parkinson's disease impair cellular antioxidative defence capacity and heighten neuronal vulnerability towards oxidative insults. α‑synuclein aggregation further amplifies intracellular ROS generation, jointly promoting degenerative damage of substantia nigra neurons.

2.5 Gut‑microbiota dysregulation and gut‑brain axis

Increasing research highlights the critical function of the gut‑brain axis in PD pathogenesis. Gut microbiota disturbance not only participates in central neuroinflammatory signal transmission, but also strongly correlates with non‑motor PD manifestations, particularly refractory constipation. Long‑term levodopa medication can disrupt intestinal flora equilibrium in PD patients, triggering over‑proliferation of harmful enteric bacteria. Remodelling intestinal microbiota composition represents a promising auxiliary intervention direction for managing non‑motor symptoms of Parkinson's disease.

2.6 Neuronal apoptosis

Apoptosis is genetically‑programmed cell death, representing the final common execution pathway for dopaminergic neuron disappearance in PD lesions. Multiple upstream pathological signals including oxidative stress, inflammation and ER stress converge to activate apoptotic cascades. Anti‑apoptotic protein Bcl‑2, pro‑apoptotic family proteins, tyrosine hydroxylase (TH) as well as neurotrophic factors such as GDNF and MANF play decisive regulatory roles in determining neuronal survival or death. Declined TH protein expression is the hallmark biomarker for dopaminergic neuron damage within PD model systems.

3. Neuroprotective Mechanisms of Cistanche deserticola Active Compounds against Parkinson's Disease

3.1 Amelioration of mitochondrial dysfunction

Mitochondrial damage is an early driving event of dopaminergic neuron degeneration. Multiple cell‑based experiments confirm that echinacoside exerts protective effects targeting mitochondrial impairment induced by neurotoxins. In 6‑OHDA‑damaged PC12 cell models, echinacoside effectively mitigates the drop of cell viability, suppresses intracellular ROS accumulation and restores collapsed mitochondrial membrane potential. When applied to SH‑SY5Y human neuroblastoma cells challenged by mitochondrial complex‑I inhibitor, echinacoside selectively rescues mitochondrial respiratory function and reverses mitochondrial depolarisation status.

Such observations indicate that Cistanche deserticola‑derived phenylethanol glycosides can stabilise mitochondrial structural integrity, restrain excessive ROS generation originating from damaged organelles, and interrupt the positive‑feedback loop between mitochondrial injury and oxidative stress. This constitutes one essential mechanism underlying its neuronal‑protective potency. Nevertheless, most existing experimental evidence originates from in‑vitro cellular systems; in‑vivo dynamic mitochondrial morphological observation at animal‑tissue level still requires further supplementary research.

3.2 Inhibition of neuroinflammatory response

Excessive glial‑cell activation and subsequent neuroinflammatory signalling constitute important pathological drivers advancing PD deterioration. MPTP‑induced PD mouse models are widely adopted to investigate anti‑neuroinflammatory pharmacological properties of echinacoside. Echinacoside can modulate p38 MAPK and NF‑κB signalling pathways, restrain over‑activation of microglia and astrocytes, and lower the secretion level of downstream pro‑inflammatory cytokines, thereby protecting substantia nigra dopaminergic neurons against inflammatory toxicity.

Apart from the classic p38 MAPK / NF‑κB axis, echinacoside also intervenes in NLRP3/CASP‑1/IL‑1β inflammasome signalling cascades. By suppressing NLRP3 inflammasome assembly and activation, it reduces maturation and release of IL‑1β inflammatory mediator and improves movement‑related behavioural deficits in PD model animals. Collectively, these pre‑clinical findings suggest inhibition of microglia‑driven neuroinflammation serves as a vital pharmacological target for Cistanche deserticola‑originated bio‑constituents in PD neuroprotection.

3.3 Regulation of endoplasmic reticulum stress

Persistent unresolved endoplasmic reticulum stress mediates substantial neuronal loss within PD pathological lesions. Multiple in‑vitro and in‑vivo experimental datasets verify that echinacoside can mitigate 6‑OHDA‑provoked endoplasmic reticulum stress injury and rescue cell viability of impaired nigrostriatal neurons. In PD‑model rat assays, echinacoside treatment down‑regulates ER‑stress marker GRP78 expression level and elevates MANF neurotrophic‑factor abundance, consequently conferring protective effects for dopaminergic nerve cells.

Seipin protein participates in ER‑stress regulatory processes; echinacoside can alleviate pathological accumulation of misfolded seipin protein triggered by neurotoxic stimuli, which further relieves downstream ER‑stress‑derived pro‑apoptotic signalling. Current investigations predominantly focus on echinacoside monomer; comparative research regarding whether verbascoside or other Cistanche deserticola components produce parallel regulatory influences upon ER‑stress pathways remains relatively scarce.

3.4 Suppression of oxidative‑stress‑mediated neuronal injury

Oxidative stress occurs throughout the whole pathological progression of Parkinson's disease. In MPP⁺‑stimulated SH‑SY5Y cellular models, echinacoside inhibits intracellular ROS generation and simultaneously reduces α‑synuclein protein expression. DJ‑1 gene mutation generates high cellular susceptibility towards oxidative damage. Studies demonstrate that Cistanche deserticola extracts and its characteristic monomers including echinacoside, verbascoside and total cistanche glycosides can enhance cell viability of H₂O₂‑treated SH‑SY5Y cells carrying pathological DJ‑1 mutation variants.

In MPTP‑induced PD mouse models, echinacoside treatment suppresses in‑vivo oxidative‑stress status and preserves dopaminergic neuron integrity. The antioxidative capacity of these compounds partly arises from their phenolic chemical structures which directly scavenge reactive free radicals; on the other hand, they modulate endogenous cellular antioxidative signalling networks. Most existing studies adopt cellular and rodent‑animal systems; human‑derived primary neuron‑based validation and clinical antioxidative biomarker observation still await further exploration.

3.5 Modulation of intestinal microbiota and gut‑brain axis‑related non‑motor symptoms

Constipation represents one of the most prevalent non‑motor symptoms among PD patient cohorts, closely associated with gut‑microbiota imbalance mediated by the gut‑brain axis. Clinical observational studies indicate that long‑term compound levodopa therapy tends to disrupt intestinal flora homeostasis in PD patients, facilitating expansion of harmful gut microorganisms.

Clinical preliminary observation suggests that combined intervention of Cistanche deserticola preparation together with compound levodopa can decrease constipation‑symptom CSS scoring in PD subjects. Meanwhile, it elevates relative abundance of beneficial enteric bacteria such as Bifidobacterium, Clostridium butyricum and Lactobacillus within patient intestinal tract. This implies that Cistanche deserticola ingredients improve PD‑associated constipation manifestations partially by remodelling intestinal‑microbiota composition. It should be noted that available clinical sample size remains limited, lacking large‑sample randomised controlled clinical trial evidence. Further high‑quality clinical research is required to validate gut‑microbiota‑regulating efficacy and corresponding molecular gut‑brain communication mechanisms.
 

3.6 Inhibition of pathological neuronal apoptosis

Apoptosis signal‑pathway over‑activation is the direct cause for massive loss of dopaminergic neurons in PD pathological lesions. In TNF‑α‑stimulated SH‑SY5Y apoptotic cell models, echinacoside increases anti‑apoptotic Bcl‑2 protein expression and restrains neuronal apoptotic progression. Tubular‑type Cistanche nano‑powder treatment augments GDNF neurotrophic factor and its receptor protein expression in the brain of PD‑model mice. Supported by GDNF‑mediated neurotrophic support, neuronal‑apoptosis events are reduced, and MPTP‑evoked behavioural dysfunction in experimental animals gets alleviated.

Echinacoside can also act upon ROS/ATF3/CHOP signalling axis to block MPTP‑provoked dopaminergic‑neuron apoptosis. Tyrosine hydroxylase (TH) is the rate‑limiting enzyme governing dopamine biosynthesis, and reduction of TH level marks functional damage of dopaminergic neurons. Total glycosides extracted from Cistanche deserticola can maintain TH‑positive neuron quantity in PD‑model mice, protect substantia nigra dopaminergic neurons and ameliorate neurobehavioural deficits in experimental animals. Multiple molecular‑level evidence confirms that suppressing apoptotic cascades constitutes one pivotal neuroprotective mode for Cistanche deserticola‑derived bio‑active substances.

4. Comprehensive Analysis of Existing Research Limitations

Current pre‑clinical experimental outputs have illustrated multi‑target neuroprotective potential of Cistanche deserticola bio‑constituents for Parkinson's disease intervention; nevertheless, multiple obvious research gaps still exist restricting translational transformation towards clinical application.

First, most mechanistic research concentrates on single‑molecule monomers, especially echinacoside. However, herbal extracts exert pharmacological effects relying on synergistic interaction among multiple composite components. Investigations addressing synergistic or antagonistic relationships between different Cistanche deserticola chemical ingredients are comparatively insufficient. Whether compound extracts produce superior neuroprotective effects over single purified monomers requires more systematic comparison.

Second, majority experimental data are obtained from in‑vitro cell models and small‑rodent animal PD models. Large‑animal model verification is very limited. Pre‑clinical studies frequently adopt acute neurotoxin‑induced injury models, which cannot fully recapitulate slow, chronic progressive pathological characteristics of idiopathic human Parkinson's disease.

Third, clinical research evidence is inadequate. Only small‑sample observational trials are accessible. There is a shortage of large‑scale, multi‑centre, randomised double‑blind controlled clinical trials to confirm clinical efficacy, optimal dosage range, long‑term safety profile and adverse‑reaction spectrum of Cistanche deserticola‑originated preparations for PD patient cohorts.

Fourth, few studies focus on pharmacokinetic behaviours including blood‑brain‑barrier penetration efficiency, in‑vivo metabolic transformation and tissue‑distribution features of these active components. Bioavailability issues may constitute a critical bottleneck for practical in‑vivo application of phenylethanol glycoside compounds. In‑depth pharmacokinetic research will lay indispensable groundwork for subsequent formulation optimisation and drug‑development work.

Fifth, the correlation between different raw‑material processing, pretreatment and drying technologies (such as ultra‑high‑pressure pretreatment, steaming, hot‑air‑drying, freeze‑drying) and final neuropharmacological activity of finished Cistanche deserticola products lacks systematic exploration. Different processing workflows change the relative abundance of various bio‑active constituents, which will further influence the actual neuro‑protective pharmacological performance of final herbal products.

5. Future Research Perspectives

In view of existing research deficiencies, follow‑up research work can be promoted from several directions.

Primarily, carry out multi‑component synergistic‑effect research. Compare neuroprotective differences between total extracts and representative monomer compounds. Dissect interaction relationships among phenylethanol glycosides, polysaccharides and other secondary metabolites, clarify multi‑component synergistic molecular mechanisms.

Secondly, expand pre‑clinical model systems. Apart from conventional cellular and mouse neurotoxin‑induced PD models, utilise chronic progressive genetic PD animal models and large‑animal models to evaluate long‑term efficacy and safety of Cistanche deserticola derived bio‑substances. Combine multi‑omics analytical approaches including transcriptomics, proteomics and metabolomics to excavate more potential intervention targets.

Thirdly, advance high‑quality clinical‑trial implementation. Design rigorous randomised controlled clinical trials, recruit sufficient PD patient participants, evaluate both motor‑symptom improvement and non‑motor‑symptom relief (especially constipation, sleep disorder). Monitor clinical‑biochemical indicators, assess long‑term safety and tolerability, provide solid clinical proof for practical therapeutic utilisation.

Fourthly, strengthen pharmacokinetic and formulation‑development research. Explore brain‑targeted delivery strategies to enhance blood‑brain‑barrier permeability of phenylethanol‑glycoside‑type components, resolve bio‑availability limitations, lay technical foundation for new neuroprotective agent development.

Fifthly, establish linkage research connecting raw‑material processing‑technology and pharmacological activity. Integrate pretreatment, dehydration and storage‑process parameters, analyse how different processing schemes alter component‑profiling and corresponding neuro‑pharmacological potency of Cistanche deserticola finished products, supplying technical support for standardised production of high‑quality neuro‑protective herbal raw‑materials.

6. Conclusion

Cistanche deserticola, the well‑known food‑medicine homologous desert herb, contains abundant phenylethanol glycosides represented by echinacoside and verbascoside, alongside polysaccharides and other bio‑active metabolites. Cumulative pre‑clinical research demonstrates that these natural ingredients implement multi‑pathway neuro‑protective functions targeting Parkinson's‑disease‑relevant pathological changes: improving mitochondrial functional defects, inhibiting microglia‑mediated neuro‑inflammatory cascades, mitigating endoplasmic‑reticulum stress, counteracting oxidative‑stress neuronal damage, regulating gut‑microbiota composition to relieve non‑motor symptoms and suppressing dopaminergic‑neuron apoptotic signalling pathways.

Even so, current investigations are still predominantly confined to cellular and rodent‑animal pre‑clinical experiments. Multiple unresolved challenges remain, such as multi‑component synergistic mechanisms, suitability of disease models, pharmacokinetic characteristics and high‑level clinical‑trial evidence. Further comprehensive and systematic research is required to push forward translational application of Cistanche deserticola‑derived bio‑active substances as neuro‑protective candidates for Parkinson's‑disease adjuvant therapy. This natural‑herbal resource possesses attractive research‑and‑development prospects for neurodegenerative‑disease intervention.

References

[1] Sveinbjornsdottir S. The clinical symptoms of Parkinson's disease. Journal of Neurochemistry. 2016;139(1):318‑324.

[2] Simon DK, Tanner CM, Brundin P. Parkinson Disease: Epidemiology, Pathology, Genetics, and Pathophysiology. Clinics in Geriatric Medicine. 2020;36(1):1‑12.

[3] Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548‑560.

[4] Wang T, Zhang X, Xie W. Cistanche deserticola Y. C. Ma, "Desert ginseng": a review. The American Journal of Chinese Medicine. 2012;40(6):1123‑1141.

[5] Gu C, Yang X, Huang L. Cistanches Herba: A Neuropharmacology Review. Frontiers in Pharmacology. 2016;7:289.

[6] Malpartida AB, Williamson M, Narendra DP, et al. Mitochondrial Dysfunction and Mitophagy in Parkinson's Disease: From Mechanism to Therapy. Trends in Biochemical Sciences. 2021;46(4):329‑343.

[7] Wang YH, Xuan ZH, Tian S, et al. Echinacoside Protects against 6‑Hydroxydopamine‑Induced Mitochondrial Dysfunction and Inflammatory Responses in PC12 Cells via Reducing ROS Production. Evidence‑Based Complementary and Alternative Medicine. 2015;2015:189239.

[8] Ma H, Liu Y, Tang L, et al. Echinacoside selectively rescues complex I inhibition‑induced mitochondrial respiratory impairment via enhancing complex II activity. Neurochemistry International. 2019;125:136‑143.

[9] Ho MS. Microglia in Parkinson's Disease. Advances in Experimental Medicine and Biology. 2019;1175:335‑353.

[10] Zhang J, Zhang Z, Xiang J, et al. Neuroprotective Effects of Echinacoside on Regulating the Stress‑Active p38MAPK and NF‑κB p52 Signals in the Mice Model of Parkinson's Disease. Neurochemical Research. 2017;42(4):975‑985.

[11] Gao MR, Wang M, Jia YY, et al. Echinacoside protects dopaminergic neurons by inhibiting NLRP3/Caspase‑1/IL‑1β signaling pathway in MPTP‑induced Parkinson's disease model. Brain Research Bulletin. 2020;164:55‑64.

[12] Li J, Yu H, Yang C, et al. Therapeutic Potential and Molecular Mechanisms of Echinacoside in Neurodegenerative Diseases. Frontiers in Pharmacology. 2022;13:841110.

[13] Zhang Y, Long H, Zhou F, et al. Echinacoside's nigrostriatal dopaminergic protection against 6‑OHDA‑Induced endoplasmic reticulum stress through reducing the accumulation of Seipin. Journal of Cellular and Molecular Medicine. 2017;21(12):3761‑3775.

[14] Trist BG, Hare DJ, Double KL. Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease. Aging Cell. 2019;18(6):e13031.

[15] An C, Pu X, Wang Q, et al. Cistanche extracts ameliorates the neurotoxicity induced by hydrogen peroxide in new mutant DJ‑1‑transfected neuroblastoma cellular models. Brain and Behavior. 2019;9(7):e01304.